Erythema is a skin condition characterized by redness or rash of the skin. It occurs with any skin injury, infection, or inflammation. It can also occur as a reaction to medications, illness or emotions. It can further occur for reasons currently unknown. Erythema is difficult to treat. Currently available treatments for erythema mainly treat the underlying diseases and avoid known triggers. These treatments are of limited effectiveness, particularly for erythema with unknown causes.
It has been described that α adrenoceptor agonists, such as brimonidine and oxymetazoline, can be used for topical treatment of erythema. See U.S. Pat. No. 7,439,241 to DeJovin et al., the priority of which is properly claimed by the present application and the disclosure of which is hereby incorporated by reference in its entirety; and U.S. Pat. No. 7,812,049 to Shanler et al.
Side effects following topical administration of an α adrenoceptor agonist, particularly those resulting from systemic exposure, may impose limitations on the chronic topical application of α adrenoceptor agonists to the skin. For example, brimonidine, available as either a monotherapy or an adjunctive therapy to lower intraocular pressure (IOP) in the treatment of glaucoma and ocular hypertension (OHT), can be absorbed systemically to a limited extent following ophthalmic application as demonstrated by reduction in blood pressure and decrease in heart rate. The most common side effects associated with brimonidine therapy are dry mouth, fatigue/drowsiness, headache, mild hyperemia, blurred vision and foreign body sensation. Hypertension, palpitations and syncope have been reported by less than 3% patients in clinical trials involving brimonidine ophthalmic treatment. See McGhie, Journal of the Pharmacy Society of Wisconsin, May/June 2001, at World Wide Web: pswi.org/professional/pharmaco/brimonidine.pdf, and references therein. Results from the dose-ranging study in patients with glaucoma or ocular hypertension showed that although 0.5% (w/w) had higher efficacy in the early phase of treatment, the 0.5% (w/w) and 0.2% (w/w) had similar efficacy after two weeks of treatment, and that 0.5% (w/w) had more systemic and ocular side effects than 0.2% (w/w). See, e.g., Walters, Survey of Ophthalmology, 1996, 41: S19-S26). Ophthalmic formulations containing 0.2% (w/w) brimonidine have been used for chronic applications to treat glaucoma and ocular hypertension, while that containing 0.5% (w/w) brimonidine has been only used for acute therapy for the prevention of postoperative intraocular pressure spikes. In order to reduce a variety of ocular and systemic side-effects associated with the ophthalmic application of 0.2% (w/w) brimonidine, ophthalmic formulations containing lower concentrations of brimonidine, e.g., 0.15% (w/w) or 0.1% (w/w), have been subsequently developed and used for chronic ophthalmic applications.
DeJovin et al. recognizes the need of a topical skin composition that insures that the α adrenoceptor agonists are effective in the skin of a patient but do not penetrate the skin in sufficient amounts to induce serious systemic side effects. It describes topical formulations containing an α adrenoceptor agonist at about 0.01% (w/w) to about 5% (w/w), preferably about 0.05% (w/w) to about 1% (w/w), more preferably about 0.1% (w/w) to about 0.2% (w/w), for treating erythema associated with rosacea. It provides examples on various possible topical formulations that can be used for topical administration of a adrenoceptor agonists, e.g., aqueous solution topical formulation, cream topical formulation, ointment formulation, and aqueous gel formulations. DeJovin et al. also includes examples demonstrating the therapeutic effectiveness of a adrenoceptor agonists, such as brimonidine, oxymetazoline and naphazoline, in treating erythema. However, it contains no example or illustration on the safety of the treatment.
To ensure the safety and avoid unacceptable side effects, a previous clinical study used 0.2% (w/w) brimonidine tartrate as the “high” dosage for treating erythema. See US 2009/0061020 to Theobald et al.
Oxymetazoline, available in 0.025% (w/w) or 0.05% (w/w) solution as a topical decongestant, has been recommended not to be used for more than three days, because rebound congestion, rhinitis medicamentosa, and other side effects may occur, see Ramey et al., J Investig Allergol Clin Immunol 2006; Vol. 16(3): 148-155.
Shanler et al. describes the use of a composition comprising about 0.05% (w/w) to about 30% (w/w), preferably about 0.001% (w/w) up to about 3% (w/w), α1 adrenoceptor agonist, such as oxymetazoline, for treating erythema resulting from rosacea. It generally describes that the “compositions according to the invention may comprise all pharmaceutical forms normally utilized for the topical route of administration and known to practitioners of this art including solutions, gels, lotions creams, ointments, foams, mousses, emulsions, microemulsions, milks, serums, aerosols, sprays, dispersions, microcapsules, vesicles and microparticles thereof.” Shanler et al. does not provide examples on possible formulations that may be used, nor examples on the effectiveness or safety of any treatment.
There remains the need of a safe and effective treatment of erythema or a related symptom by using a topical skin composition that delivers a therapeutically effective amount of a adrenoceptor agonist to the affected skin area without causing unacceptable side effects.
In the present invention, it has been discovered that topical administration to an affected skin area an α adrenoceptor agonist, such as brimonidine, in a topical aqueous gel composition resulted in significantly less systemic exposure than topical ophthalmic application. It has been found that although systemic exposure increased with the applied dose of brimonidine, statistical analysis showed that the increase in systemic exposure (Cmax) was not dose proportional, i.e., the increase in the mean Cmax was much less than the increase in the dose. It has also been discovered that, unlike the topical ophthalmic application, topical administration to an affected skin area a higher concentration of an α adrenoceptor agonist, such as 0.5% (w/w) brimonidine, in a topical aqueous gel composition resulted in increased efficacy without observable loss of effectiveness over time. No unacceptable adverse event was observed with the treatment of higher concentration of an α-adrenergic receptor agonist tested.
Accordingly, it has unexpectedly been discovered that a topical aqueous gel composition has achieved superior clinical properties, e.g., allowing more effective treatment of erythema without causing unacceptable side effect, even at higher concentrations of the α adrenoceptor agonist.